Introduction

Diabetes mellitus (DM) is referred to as heterogeneous disturbances of metabolism characterized by chronic hyperglycemia, which is caused by either insufficient insulin secretion in the pancreatic β-cells (type-1 diabetes mellitus (T1D)) or impaired insulin secretion and action (type-2 diabetes mellitus (T2D)) [1]. The disease and its complications continue to be a major global health threat [2]. In 2017, DM-associated complications resulted in approximately 4 million deaths worldwide and accounted for 6.8% of total deaths in Africa [3]. Additionally, DM is predicted to be among the top seven causes of death by 2030 [4]. The prevalence of DM has increased exponentially worldwide in the last four decades [5, 6], which is mainly attributed to the growing and aging population, high energy/high fat diet, as well as sedentary lifestyle [7]. Notably, more than 90% of all DM cases are T2D [8] and according to Noubiap et al. [9], approximately 425 million DM cases were recorded in 2017 globally. The caseload is predicted to increase by 48% with an estimated 629 million affected individuals by 2045 [9]. In the African population, approximately 19.8 million DM cases are recorded, and it is estimated that 75% of them have not been diagnosed [10]. The prevalence of DM and impaired glucose tolerance is approximately 4.1% and 6.6%, respectively, in Uganda [10]. Moreover, the prevalence of DM in Uganda is projected to increase by 166.9% between 2013 and 2035, which will exceed the prevalence of DM in most other countries [11]. The management and treatment of DM are challenging as currently available conventional drugs, like acarbose are expensive, inaccessible, associated with several undesirable side effects, and have high secondary treatment failure rates [12]. Moreover, a definitive cure for DM is currently unavailable [13]. To overcome these challenges in the management and treatment of DM, there is a need to employ multiple approaches to identify alternative therapeutic strategies. Medicinal plants have been historically used to treat and manage DM in several traditional medicine systems of many cultures worldwide, especially in developing countries such as Uganda [12]. The use of medicinal plants is popular for primary health care among the general population owing to cultural acceptability, compatibility with the human body, and less side effects [14]. The World Health Organization has recommended the use of medicinal plants for managing DM and suggested increased efforts to scientifically evaluate the hypoglycemic properties of diverse plant species [13]. Ethnopharmacological studies are, by definition, scientific approaches to the study of biological activities of preparations used by humans, which possess, either beneficial or toxic or other direct pharmacological effects [15] and thus, ethnopharmacology involves investigating the relationship between humans and plants in all its complexity [15]. Accordingly, several ethnobotanical surveys conducted in Uganda have revealed that various medicinal plants are used in the management of DM [16,17,18,19,20,21,22,23,24]. Indeed, ethnopharmacological studies have reported the anti-diabetic efficacy of some of these plants and their derived formulations [23, 25]. However, these information remain highly fragmented without a single repository for plants used in the management and treatment of DM in Uganda, hindering further investigations. Therefore, this review aimed to explore plants used for treatment and management of DM in Uganda including relevant ethnopharmacological and ethnomedicinal information, which could provide useful information for research on DM therapy.

Methods

To get information on medicinal plants used in the management and treatment of DM in Uganda, Scientific databases namely, PubMed, Scopus, Google Scholar, Science Direct, SciFinder, and Medline were searched to retrieve relevant English peer-reviewed articles and books. Additional articles were found after tracking citations of the already accessed publications. Various attributes captured included species, family, local name, parts used, mode of preparation, habitat, and other diseases treated. Following this, the same databases were searched to obtain information on the anti-diabetic potential and safety of the identified plants. In this regard, research articles reporting anti-diabetic activities and safety of these plants were reviewed and findings recorded. During the search process, initially, the key words; ‘’ethnomedicine’’, ‘’ethnopharmacology’’, ‘’traditional medicine’’, ‘’herbal medicine’’, ‘’medicinal plant’’, ‘’phytomedicine”, ‘’ethnobotany’’ were combined with “diabetes mellitus”, “Uganda”. Next, each plant name identified from the above search were paired with “phytochemicals”, ‘’extract’’, ‘’isolation’’, ‘’efficacy’’, ‘’safety’’, ‘’toxicity’’, “antidiabetic”, “diabetes mellitus”, “hyperglycemic”, “hypoglycemic”, “mechanism of action,” “antihyperglycemic”, ‘’antilipidemic’’. The medicinal plants were then categorized based on their anti-diabetic activity investigation status. Additionally, ethnomedicinal uses of the identified plants in other countries neighbouring Uganda namely, Kenya, Tanzania, Democratic Republic of the Congo, Rwanda, and Sudan were obtained. Thereafter, the collected data were summarized and presented accordingly.

Results and discussion

Traditional concept of DM in Uganda

Generally, the understanding of DM is associated with several misconceptions, including its prevention, causes, signs, and treatment. A large portion of the population is aware of DM, especially in urban areas. However, nonfactual information on DM exists in the Ugandan population. For instance, DM symptoms are associated with witchcraft [26] and most people seek medical help when the symptoms of DM are severe, resulting in increased morbidity and mortality [27]. The use of traditional medicine inluding medicinal plants for treatment of DM is widespread in Uganda [28].

Plants used for treating DM in Uganda

The literature review identified 46 species of plants belonging to 26 families that are used to treat DM in Uganda (Table 1). The most commonly used species belonged to the Fabaceae (20%), Asteraceae (13%), and Solanaceae (7%) families (Fig. 1). The predominant use of plant species from these families to treat DM and its complications is attributed to a wide range of bioactive compounds, which make them largely effective in the treatment of human diseases [29, 30]. The widespread use of medicinal plants for DM treatment and management among the Ugandan population is due to low cost, easy accessibility, cultural acceptability, and the perceived less side effects [28]. This suggests that medicinal plants are key alternatives to the currently available conventional DM medicines. Consistent with our findings, several other researchers have also reported dominant use of plant species belonging to Fabaceae and Asteraceae families for treatment of DM in other countries, such as Nigeria and Tanzania [13, 31, 32]. Furthermore, studies have also shown that same plants are used similarly for DM treatment in neighboring and other countries (Table 2), for instance, the use of Erythrina abyssinica DC. (Fabaceae) and Bidens pilosa L. (Asteraceae) for treatment of DM were reported in Kenya [31]. Vernonia amygdalina Del., Aspilia africana (Pers.) C.D.Adams, and Ageratum conyzoides (L.) L. (all in Asteraceae) were documented to be used traditionally for treating DM in Nigeria [31, 33]. Cajanus cajan (L.) Huth (Fabaceae) has been used to treat DM in Tanzania [32].

Table 1 Plants used for traditionally treating diabetes mellitus in Uganda based on ethnobotanical surveys
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Fig. 1
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Distribution of medicinal plant families used for treating diabetes mellitus in Uganda

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Table 2 Ethnomedicinal uses of the identified plants in other countries neighbouring Uganda
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Plant parts used, preparation, and mode of administration

The leaf (44%) was the most commonly used part, followed by the root (20%), fruit (12%), seed (9%), stem (8%), whole plant (3%), flowers (2%), and other unspecified parts (2%) (Fig. 2). The high use of leaves for DM treatment compared to other plant parts might be accounted to their potency associated with higher accumulation of bioactive compounds, ease of harvest, and quick ability to regenerate [30]. The extensive use of leaves for the treatment of DM corroborates with the findings of Skalli et al. [104] and Mohammed et al. [31] who also reported highest use of leaves for DM management compared to other plant parts. The most common modes of herbal preparation include decoction [17, 24] and infusion [21, 24] (Table 1). Decoctions are prepared by boiling plant materials in a specific quantity of water for 15–20 min and after, the mixtures are allowed to cool before administration. For example, Canarium schweinfurthii Engl. (stem barks), Cymbopogon citratus Stapf (leaves), Cajanus cajan (L.) Huth (leaves), and Hallea rubrostipulata (K. Schum.) J-F. Leroy (roots) are all prepared by decoction before administration. Infusion involves pouring hot or warm water onto the plant material and allowing the mixture to cool prior to administration. Plants such as Bidens pilosa L. (leaves, whole plant, roots) and Schkuhria pinnata (Lam.) Kuntze ex Thell. (leaves) are prepared through infusion for treatment of DM. Meanwhile, example of plants that are consumed directly for purposes of treating DM include Oxalis corniculata L. and Carissa macrocarpa (Eckl.) A.DC.. As observed, some medicinal plant parts are prepared through maceration; this involves crushing plant materials of a single species or a combination to extract a liquid before consumption. A case in point is Vigna unguiculata (L.) Walp. preparation. The common employment of decoction as a mode of preparation is attributed to the fact that boiling enables extraction of ingredients and preserves the herbal remedy longer compared to when cold water is used [30]. In some instances, other methods of preparation are more valuable because boiling leads to remarkable degradation of phytochemicals more so, aromatic compounds when done for a longer time [30]. This implies that no single mode of extraction is suitable for all medicinal plant preparation. Several other studies have reported similar modes of herbal preparation for treatment of DM [13, 31]. The solvent used for these herbal preparations is water and all prepared herbal medicines for DM treatment are orally administered (Table 1). Worth mentioning is that majority of these plants (about 63%) are obtained from the wild (Table 1). This is an indication that there is heavy dependence on wild source or natural environment in obtaining these medicinal plants; suggesting need to adopt propagation strategies (both macro and micro methods) for the plants for massive and sustainable supply of these medicinal materials. This finding is consistent with ethnobotanical study reports from other countries including Mexico [105], Ethiopia [106], and Turkey [107].

Fig. 2
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Percentage use of different plant parts for treatment of diabetes mellitus in Uganda

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Knowledge dynamics of antidiabetic plants in Uganda

Through generations, knowledge of traditional medicine and medicinal plants are orally transferred from elders to young ones in Uganda [108]. Similar trend of traditional medicine knowledge transfer has been recorded in other African countries like Kenya and Ghana [109, 110]. At present, to the best of our knowledge, there are no exclusive indigenous knowledge systems or databases for Ugandan traditional medicines, except the highly fragmented reports of ethnobotanical studies conducted in Uganda. However, at African level, some active databases for African traditional medicine are available with non being specific to DM or any other disease (Table 3). Consequently, due to a wide range of biodiversity among countries, antidiabetic use of most plants registered in this study are not found in these general databases; although some plants are available with similar uses. For example, use of Acacia constricta for treatment of DM and other ailments is documented in PRELUDE database while use of Albizia chinensis for treatment of DM in the same database is not found currently. Considering the biodiversity difference among countries, development of comprehensive indigenous knowledge systems for African traditional medicine requires more efforts towards documenting these knowledge at country and subsequently regional (East, North, West, and South African) levels. The unavailability of Ugandan and limited African traditional medicine databases or records may be attributed to several factors among others, difficulty associated with language translation as most countries are made of diverse population with various languages, lack of funds for establishment and maintenance, and issues of intellectual property right [111]. In fact, insufficient or lack of funding has made several indigenous knowledge systems for traditional medicine become less updated or/and inactive online. For instance, a database known as NTRAP (Website: http://www.ippc.orst.edu/ipmafrica/db/index.html) that contained traditional medicine indigenous knowledge for East Africa (Uganda inclusive) is currently inactive [111].

Table 3 List of some active African Traditional Medicine Databases
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Ethnopharmacological activities of medicinal plants used for treating DM in Uganda based on global scientific investigations

In vitro and in vivo studies

According to the WHO Traditional Medicine Strategy objectives, experimental validation with specified doses is the only way for proper understanding of the safety and efficacy of herbal medicines despite their long traditional use [114]. With respect to DM, the typical clinical target is to reduce blood sugar [115]. Therefore, the in vivo evaluation of blood sugar lowering effect of medicinal plants is for inferring potential clinical efficacy. In vitro studies are useful in the establishment or verification of the mechanisms of action of substances with potential therapeutic effects including medicinal plants [115]. Twenty seven (59%) out of the forty six medicinal plants in this review have been evaluated for their pharmacological activities against DM in several in vitro and in vivo studies worldwide (Table 4). Indeed, these plants have shown significant pharmacological activities including anti-hyperglycemic, anti-lipidemic, and antioxidative properties.

Table 4 Anti-diabetic, anti-lipidemic, and antioxidative properties of medicinal plants used for treating DM in Uganda based on global scientific investigations
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Taken together, these ethnopharmacological activities were exerted through various mechanisms of action. The mechanisms of action included decreasing blood sugar via stimulation of pancreatic β-cells [116, 117], inhibition of α-amylase, α-glucosidase, DPP-IV, insulinase, and aldose reductase enzymes activities [118,119,120,121], increasing expression of glucose transporters [122, 123], and enhancement of the affinity as well as sensitivity of insulin receptors [124]. Additionally, the plants acted through increase of glucose utilization within several tissues and organs [125], resistance of lipid peroxidation [126,127,128], clearance of free radical [127], and correction of lipid as well as protein metabolic disorders [129,130,131]. The observed mechanisms of action are comparable to those of current drugs used in DM treatment. For example, plants such as Syzygium cumini (L.) Skeels and Kigelia africana (Lam.) Benth., with α-amylase and α-glucosidase inhibitory effects are similar in action to acarbose [132]. Stimulators of pancreatic β-cells, for instance Tithonia diversifolia (Hemsl.) A.Gray and Bidens pilosa L. function as sulfonylureas or non-sulfonylureas secretagogues classes of drugs [115]. Plants like Schkuhria pinnata (Lam.) Kuntze ex Thell. which increase glucose utilization within tissues and organs are comparable to the biguanides drugs [115]. Agonists of PPARγ, for instance, Tithonian diversifolia (Hemsl.) A.Gray are similar in action with thiazolidinediones class of hypoglycemic agents [132]. Thus, the known mechanisms of action of the antidiabetic medicinal plants provide prospective therapeutic benefits of the plants, which may be utilized in the development of DM therapy. Medicinal plants studied elsewhere such as Chiliadenus iphionoides (Boiss. & C.I.Blanche) Brullo, Prunus africana (Hook.f.) Kalkman, Aspilia africana (Pers.) C.D.Adams, Cassia fistula L., and Ocimum gratissimum L. were reported to exhibit similar mechanisms of action against DM [33, 104, 132,133,134].

Phytochemicals in these plants either singly or in combination have been implicated for their antidiabetic properties [135, 136]. In fact, antidiabetic effects of plants are attributed to several classes of compounds namely, alkaloids, phenolic acids, saponins, tannins, and terpenoids [127, 137, 138]. A case in point is Jassim et al. [139] who reported that phenol extracts of Solanum melongena L. peels decreased blood glucose, triglyceride, blood total cholesterol, and low-density lipoprotein levels alongside increased serum high density lipoprotein levels in diabetic rats. Furthermore, the extract promoted hepatic detoxification by decreasing levels of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvic transaminase (SGPT) in alloxanised diabetic albino rats [139]. Interestingly, successful isolation, characterization, and purification of some antidiabetic phytoconstituents from a few plants have been achieved [119, 125, 140,141,142] (Table 4). For example, thyrotundin and tagitinin A were isolated from Tithonian diversifolia (Hemsl.) A.Gray with confirmed effect of decreasing insulin resistance via upregulating PPARγ activity [140]. In another study, Watanabe et al. [143] reported that aculeatin isolated from Toddalia asiatica (L.) Lam. promoted the differentiation and lipolysis of 3T3-L1 adipocytes along with increased glucose uptake, which are critical for treatment of DM and associated conditions. This implies that these phytochemical compounds could be potential antidiabetic agents.

Essentially, bioactive compounds of some of the investigated plants in this study have produced antidiabetic effects by acting on specific targets (For example, agonists of PPARγ such as Citrus sinensis (L.) Osbeck) [124], while other researchers only reported antidiabetic activities without definite pharmaceutical targets [144, 145]. For successful drug development, it is pivotal to identify and select targets of therapeutic compounds. Accordingly, the bioactive principles bind selectively to the receptor on the target and trigger the desired functional response [146]. In this way, molecular interactions associated with the products are understood, enabling gain of knowledge on the mechanisms of action, a key feature in a drug discovery process. Therefore, it is crucial to establish pharmaceutical targets of these herb bioactive compounds for improved outcome and development.

Regarding medicinal plants with unspecified mechanism of action such as Solanum indicum Roxb., their mechanisms of action in the DM pathway could possibly be linked to constituent phytochemicals [146]. In this case, plants with flavonoids as major bioactive compounds decrease level of blood glucose, cholesterol, and triglycerides by increasing activity of hepatic glucokinase and enhancement of insulin release from pancreatic islets [147]. Ibrahim et al. [148] isolated luteolin (3′,4′,5,7-tetrahydroxy flavone) along with other flavonoids from Oxalis corniculata L. and this compound has been reported to possess appreciable antidiabetic potential [149, 150]. Indeed, the underlying antidiabetic mechanisms and signalling pathways of luteolin include improving the sensitivity of body cells to insulin, antioxidative effect, inhibition of enzymes like PTP1B among others [149, 150]. Luteolin exerts its antioxidant properties by scavenging ROS and inhibiting enzymes responsible for ROS generation; this protects the pancreas and promotes insulin secretion [150]. Furthermore, luteolin enhances insulin sensitivity through influencing the Akt2 kinase [151]. Accordingly, Akt2 prevents the dephosphorylation of the insulin receptor and in this way, attenuation of insulin-signaling process is prevented [151]. On the other hand, plants with alkaloids as lead compounds show inhibition of α-glucosidase and decrease glucose transport through the intestinal epithelium [146]. Based on this, antidiabetic activities of plants containing high content of alkaloids in this review for instance, Ageratum conyzoides L. [152], may possibly be via lowering blood glucose and α-glucosidase inhibition. Additionally, quinolizidine alkaloids like multiflorine and sparteine have been reported to have insulinotropic effects on isolated pancreatic islets, besides their blood glucose-lowering role [153]. In fact, Wiedenfeld and Röder [154] isolated and identified multiflorine from A. conyzoides, therefore, the plant may act in the DM pathway via mechanisms related to that of multiflorine. Antidiabetic plants with bioactive principles in the classes of saponin (For example, Solanum indicum Roxb.), polysaccharides, and ferulic acid may trigger insulin secretion by stimulating pancreatic β-cells [147]. Particularly, hypoglycemic action of saponin is realised through various pathways including improvement of insulin signalling, activation of glycogen synthesis, restoration of insulin response, gluconeogenesis inhibition, among others [153, 155]. Likewise, coumarins have hypoglycemic characteristics and inhibit aldose reductase enzyme as well as aggregation of platelet [153]. Relatedly, antidiabetic plants containing high content of dietary fibers such as Cajanus cajan (L.) Huth could act by inhibiting α-amylase and delaying glucose diffusion, which in turn cause decrease in glucose absorption rate and postprandial serum glucose [146]. However, these suggested mechanisms of action can only be validated through further scientific investigations.

Meanwhile, to the best of our knowledge, 19 (41%) of the reported medicinal plant species in this study such as Justicia betonica L., Warburgia ugandensis Sprague, and Garcinia buchananii Baker remain scientifically uninvestigated for their antidiabetic effects, yet used traditionally for DM treatment. Such plants could be potential sources of active ingredients for therapy of DM and its complications, hence need for evaluation of their antidiabetic properties.

Clinical studies

Clinical trials with medicinal plants on human subjects is a critical step in drug discovery [115]. Currently, no clinical study using standardized extracts, bioactive compounds, and preparations of medicinal plants against DM has been reported in Uganda. Globally, seven medicinal plants in this review have been subjected to clinical studies involving human subjects. These plants include Moringa oleifera Lam., Artocarpus heterophyllus Lam., Bidens pilosa L., and Indigofera arrecta Hochst. ex A. Rich. among others [25, 172, 193, 295] (Table 4). Accordingly, all the tested plants showed the desired clinical effects [25, 172, 193, 295]. These therapeutic effects justify the use of the plants traditionally to treat DM across different communities in Uganda [17, 23]. However, the clinical trials were preliminary in nature aimed at assessing therapeutic effect of these plants in human subjects with none being a randomized, controlled trial. In Uganda, the absence of clinical trials on DM with traditionally used preparations may be attributed to insufficient data generated from preclinical studies, huge financial and strict regulatory requirements associated with clinical studies [296]. This means, clinical safety and efficacy of preparations from plants traditionally used to treat DM in Uganda are yet to be unlocked. The observed therapeutic effects of the evaluated plants, indicate the need to further investigate the traditionally used preparations in DM therapy for drug discovery and development.

Other ethnomedicinal uses and toxicity of the reported antidiabetic plants

Most of the plants in this review are used to treat several other diseases apart from DM (Table 1). A classic example is Kigelia africana (Lam.) Benth. which is recorded to be used for treating various health problems such as diarrhea, malaria, and cancer across different communities [19]. As such, pharmacological efficacy of K. africana against cancer has also been reported, for instance, its seed oil suppressed human embryonic kidney (HEK-293) cell and human colon adenocarcinoma (Caco-2) cell dose dependently [297]. Several active phytochemicals of K. africana have been identified and some isolated, namely, β-sitosterol, specioside, lapachol, verminoside, 3-(2′- hydroxyethyl)-5-(2″-hydroxypropyl) dihydrofuran-2-(3H)one, kigelin minecoside, ferulic acid, and 1,3-dimethylkigelin [296]. Therefore, the diverse bioactive compounds in these plants may explain their multipurpose use in treatment of diseases [115].

Besides exerting pharmacological activity that can be utilized for therapeutic purposes, constituent phytochemicals of medicinal plants are known to interact with same or other receptors and consequently produce harmful toxic effects [298]. Toxic compounds from plants may affect vital human organs and key body functional systems such as the central nervous system resulting in altered coordination of nerve functions [299]. Most of the recapitulated plants in this review have exhibited no adverse toxic effect as per respective toxicity reports (Table 4). For instance, aqueous leaf extract of Indigofera arrecta Hochst. ex A. Rich. showed no acute (up to 10 g/kg body weight, orally administered) and subchronic toxicity (2 g/kg body weight, orally administered daily for 30 days) in mice [300]. Furthermore, the extract never altered the glutathione and hepatic cytochrome P450 (CYP) isozymes whose modulation can consequently lead to interactions of components in a multiple drug treatment [300]. In another study, oral administration of leaf aqueous extract of Indigofera arrecta did not exert nephrotoxicity in humans [295]. However, some of the plants in this review have shown potential toxicity properties. Notably, Annona muricata L. fruit and leaf extracts (106 mg/kg body weight, infused intravenously for 28 days) exhibited acute neurotoxicity in rats [243]. The degree of plant toxicity depends on several factors including route of administration, method of extraction/ preparation, plant growth stage or part, victim susceptibility, species, and dosage [298]. Some phytochemicals in these plants such as anthraquinones and annonacin in Aloe vera (L.) Burm.f. and Annona muricata, respectively have been implicated for their toxicity [228, 229, 237, 243]. In cases where toxic effects are exerted at high doses, administration of preparations should be within known safe dose ranges to minimize side effects. High-risk patients like children, the elderly, pregnant women, and people with congestive heart failure ought to be more cautious when using these herbal medicines. Many other researchers around the world have provided useful information including dosages and toxicity from preclinical and clinical studies of medicinal plants, which may be relevant for development of DM therapeutic products [31, 32, 132]. It is worth noting that there is paucity of information regarding safety/toxicity profiles of the plants in this review. Moreover, most of the reported toxicity studies tested only acute toxicity either in vitro or in vivo yet this may not reflect toxicity condition experienced when taking herbal preparation for a long time as is the case in chronic diseases like DM [301]. Therefore, there is need to conduct comprehensive (acute, sub-chronic, and chronic) safety/toxicity studies on most of these potential medicinal plants to ascertain possible toxic effects to humans [302].